Merchel Piovesan Pereira Beatriz, Wang Xiaokang, Tagkopoulos Ilias
Microbiology Graduate Group, University of California, Davis, Davis, CA, United States.
Genome Center, University of California, Davis, Davis, CA, United States.
Front Microbiol. 2021 Feb 26;12:640923. doi: 10.3389/fmicb.2021.640923. eCollection 2021.
Biocide use is essential and ubiquitous, exposing microbes to sub-inhibitory concentrations of antiseptics, disinfectants, and preservatives. This can lead to the emergence of biocide resistance, and more importantly, potential cross-resistance to antibiotics, although the degree, frequency, and mechanisms that give rise to this phenomenon are still unclear. Here, we systematically performed adaptive laboratory evolution of the gut bacteria in the presence of sub-inhibitory, constant concentrations of ten widespread biocides. Our results show that 17 out of 40 evolved strains (43%) also decreased the susceptibility to medically relevant antibiotics. Through whole-genome sequencing, we identified mutations related to multidrug efflux proteins ( and ), porins ( and ), and RNA polymerase ( and ), as mechanisms behind the resulting (cross)resistance. We also report an association of several genes (, , , , , and -) and specific mutations that induce cross-resistance, verified through mutation repairs. A greater capacity for biofilm formation with respect to the parent strain was also a common feature in 11 out of 17 (65%) cross-resistant strains. Evolution in the biocides chlorophene, benzalkonium chloride, glutaraldehyde, and chlorhexidine had the most impact in antibiotic susceptibility, while hydrogen peroxide and povidone-iodine the least. No cross-resistance to antibiotics was observed for isopropanol, ethanol, sodium hypochlorite, and peracetic acid. This work reinforces the link between exposure to biocides and the potential for cross-resistance to antibiotics, presents evidence on the underlying mechanisms of action, and provides a prioritized list of biocides that are of greater concern for public safety from the perspective of antibiotic resistance.
Bacterial resistance and decreased susceptibility to antimicrobials is of utmost concern. There is evidence that improper biocide (antiseptic and disinfectant) use and discard may select for bacteria cross-resistant to antibiotics. Understanding the cross-resistance emergence and the risks associated with each of those chemicals is relevant for proper applications and recommendations. Our work establishes that not all biocides are equal when it comes to their risk of inducing antibiotic resistance; it provides evidence on the mechanisms of cross-resistance and a risk assessment of the biocides concerning antibiotic resistance under residual sub-inhibitory concentrations.
杀菌剂的使用至关重要且无处不在，使微生物暴露于亚抑制浓度的防腐剂、消毒剂和防腐剂中。这可能导致杀菌剂耐药性的出现，更重要的是，可能导致对抗生素的潜在交叉耐药性，尽管导致这种现象的程度、频率和机制仍不清楚。在这里，我们在亚抑制、恒定浓度的十种广泛使用的杀菌剂存在的情况下，系统地对肠道细菌进行了适应性实验室进化。我们的结果表明，40个进化菌株中有17个（43%）也降低了对医学相关抗生素的敏感性。通过全基因组测序，我们确定了与多药外排蛋白（和）、孔蛋白（和）以及RNA聚合酶（和）相关的突变，作为产生（交叉）耐药性的机制。我们还报告了几个基因（、、、、和 -）与诱导交叉耐药性的特定突变之间的关联，并通过突变修复进行了验证。与亲本菌株相比，更大的生物膜形成能力也是17个交叉耐药菌株中11个（65%）的共同特征。在杀菌剂氯己定、苯扎氯铵、戊二醛和洗必泰中进化对抗生素敏感性的影响最大，而过氧化氢和聚维酮碘的影响最小。未观察到异丙醇、乙醇、次氯酸钠和过氧乙酸对抗生素的交叉耐药性。这项工作加强了接触杀菌剂与抗生素交叉耐药性可能性之间的联系，提供了潜在作用机制的证据，并从抗生素耐药性的角度提供了一份对公共安全更令人担忧的杀菌剂优先清单。
细菌耐药性和对抗微生物剂敏感性的降低是极为令人担忧的问题。有证据表明，不当使用和丢弃杀菌剂（防腐剂和消毒剂）可能会选择出对抗生素具有交叉耐药性的细菌。了解交叉耐药性的出现以及与每种化学物质相关的风险对于正确应用和建议至关重要。我们的工作表明，就诱导抗生素耐药性的风险而言，并非所有杀菌剂都是相同的；它提供了交叉耐药性机制的证据以及在残留亚抑制浓度下杀菌剂对抗生素耐药性的风险评估。
